Biomedical subjects

Yiwei Liu

Publications and source records attributed to Yiwei Liu.

At least 19 recordsLinked to original sources

PubMed2026

First-line fecal microbiota transplantation for the management of immune checkpoint inhibitor-mediated diarrhea and colitis.

Immune checkpoint inhibitor (ICI) therapy commonly leads to adverse events such as ICI-mediated diarrhea and colitis (IMDC). Fecal microbiota transplantation (FMT) remains an option for patients with refractory colitis. We report a multi-omics profiling of patients receiving first-line FMT for IMDC. In our preliminary analysis, 10 (76.9%) patients achieve clinical response, with a median time to clinical improvement of 1.5 (1-10.5) days. Among responder patients with baseline and follow-up samples, 6 (75%) show an increase in alpha-diversity post-FMT. Pre-FMT samples show an increase in the abundance scores of plasma cells, neutrophils, macrophages (M1 and M2), memory activated and resting memory CD4+ T cells, CD8+ T cells, T follicular helper (Tfh) cells, and regulatory T cells (Tregs), all of which decrease post-FMT. In a small cohort of patients, we identify potential mechanisms for FMT response and demonstrate that first-line FMT in patients with IMDC (NCT04038619) can be effective.

FMT↗

PubMed2026

Dissecting the shared genetic architecture between migraine subtypes and cardiovascular diseases: a multi-layered genomic analysis.

BACKGROUND: Epidemiological studies have linked migraine to an increased risk of cardiovascular disease (CVD); however, the shared genetic basis and putative causal relationships between migraine subtypes and cardiovascular traits remain poorly understood. METHODS: Leveraging large-scale GWAS summary statistics for migraine phenotypes (overall migraine, migraine with aura [MA], and migraine without aura [MO]) from FinnGen R12, along with seven cardiovascular diseases from publicly available consortia, we conducted a multi-layered genetic analysis. This integrative framework encompassed genetic correlation [linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL)], cross-trait meta-analysis (CPASSOC and PLACO), Bayesian colocalization, summary-data-based Mendelian randomization (SMR) using GTEx v8 eQTL data, and bidirectional two-sample Mendelian randomization (MR). RESULTS: Significant genetic correlations were identified between migraine and multiple cardiovascular traits, with hypertension and coronary artery disease (CAD) showing the most robust associations. MA exhibited broader genetic overlap with cardiovascular diseases than MO, including a notably stronger correlation with ischemic stroke, whereas MO demonstrated a stronger correlation with hypertension. Cross-trait meta-analysis identified 160 pleiotropic loci across 17 of 21 trait pairs. Colocalization analysis confirmed 32 loci harboring shared causal variants, mapped to 13 candidate genes, of which 7 (PHACTR1, LRP1, SOX7, ABO, FHOD3, MEI1, XKR6) were further validated by SMR as exhibiting tissue-specific regulatory effects. Among these, PHACTR1 displayed the broadest pleiotropic profile across migraine phenotypes and vascular diseases. After MR-PRESSO outlier removal, bidirectional MR identified 10 MR-supported associations, two of which (genetic liability to hypertension on overall migraine, and CAD on MA) survived Bonferroni correction, all free of detectable horizontal pleiotropy. Genetic liability to hypertension was associated with increased migraine risk (OR = 1.90, 95% CI 1.25-2.90, P = 2.64 × 10⁻³), atherosclerotic diseases showed subtype-specific effects (inverse for MO, positive for MA), and, in the reverse direction, migraine was associated with increased ischemic stroke risk. CONCLUSIONS: This study provides a comprehensive and systematic characterization of the shared genetic architecture between migraine subtypes and cardiovascular diseases. By identifying pleiotropic genes and bidirectional putative causal relationships with subtype-specific patterns, our findings carry implications for the development of targeted therapeutics and subtype-specific cardiovascular risk stratification.

Humans↗

PubMed2007

First glimpse of the peptide presentation by rhesus macaque MHC class I: crystal structures of Mamu-A*01 complexed with two immunogenic SIV epitopes and insights into CTL escape.

The infection of rhesus macaques (Macaca mulatta) by the SIV is the best animal model for studying HIV infection and for AIDS vaccine development. A prevalent MHC class I allele, Mamu-A*01, is known to correlate with containment of SIV, which has been extensively explored in studies of CTL-based vaccination concepts. We determined the crystal structures of Mamu-A*01 complexed with two immunodominant SIV epitopes: the nonamer CM9 of group-specific Ag (Gag, 181-189; CTPYDINQM) and the octamer TL8 of transcription activator (Tat, 28-35; TTPESANL). The overall structures of the two Mamu-A*01 complexes are similar to other MHC class I molecules. Both structures confirm the presence of an absolutely conserved proline anchor residue in the P3 position of the Ag, bound to a D pocket of the Mamu-A*01 H chain with optimal surface complementarity. Like other MHC/peptide complex structures, the P2 and C-terminal residues of the epitopes are also important for anchoring to the MHC molecule, whereas the middle residues form an arch and their side chains are directed into solvent. These two structures reveal details of how Mamu-A*01 interacts with two well-studied epitopes at the atomic level. We discuss the structural basis of CTL escape, based on molecular models made possible by these two structures. The results we present in this study are most relevant for the rational design of Mamu-A*01-restricted CTL epitopes with improved binding, as a step toward development of AIDS vaccines.

Amino Acid Sequence↗

PubMed2006

Structural basis of Robo proline-rich motif recognition by the srGAP1 Src homology 3 domain in the Slit-Robo signaling pathway.

The Slit-Robo (sr) GTPase-activating protein (GAPs) are important components in the intracellular pathway mediating Slit-Robo signaling in axon guidance and cell migration. We report the first crystal structure of the srGAP1 SH3 domain at 1.8-A resolution. The unusual side chain conformation of the conserved Phe-13 in the P1 pocket renders the ligand binding pocket shallow and narrow, which contributes toward the low binding affinity. Moreover, the opposing electrostatic charge and the hydrophobic properties of the P3 specificity pocket are consistent with the observed binding characteristics of the srGAP1 SH3 domain to its ligand. Surface plasmon resonance experiments indicate that the srGAP1 SH3 domain interacts with its natural ligand inaCtoN orientation. The srGAP1 SH3 domain can bind to both the CC2 and CC3 motifs in vitro. The N-terminal two acidic residues in the CC3 motif recognition site are necessary for srGAP1 SH3 domain binding. A longer CC3 peptide (CC3-FL) binds with greater affinity than its shorter counterpart, suggesting that the residues surrounding the proline-rich core are important for protein-peptide interactions. Our study reveals previously unknown properties of the srGAP-Robo interaction. Our data provide a structural basis for the srGAP-Robo interaction, consistent with the role of the Robo intracellular domain in interacting with other downstream signaling molecules and mediating versatile and dynamic responses to axon guidance and cell migration cues.

Amino Acid Motifs↗

PubMed2006

The effect of decreasing alkalinity on microbial community dynamics in a sulfate-reducing bioreactor as analyzed by PCR-SSCP.

PCR-single-strand conformation polymorphism (SSCP) and Southern blotting techniques were adopted to investigate microbial community dynamics in a sulfate-reducing bioreactor caused by decreasing influent alkalinity. Experimental results indicated that the sulfate-removal rate approached 87% in 25 d under the conditions of influent alkalinity of 4000 mg/L (as CaCO3) and sulfate-loading rate of 4.8 g/(L*d), which indicated that the bioreactor started up successfully. The analysis of microbial community structure in this stage showed that Lactococcus sp., Anaerofilum sp. and Kluyvera sp. were dominant populations. It was found that when influent alkalinity reduced to 1000 mg/L, sulfate-removal rate decreased rapidly to 35% in 3 d. Then influent alkalinity was increased to 3000 mg/L, the sulfate-removal rate rose to 55%. Under these conditions, the populations of Dysgonomonas sp., Sporobacte sp., Obesumbacterium sp. and Clostridium sp. got to rich, which predominated in the community together with Lactococcus sp., Anaerofilum sp. and Kluyvera sp. However, when the alkalinity was decreased to 1500 mg/L, the sulfate-removal rate rose to and kept stable at 70% and populations of Dysgonomonas sp., Sporobacter sp. and Obesumbacterium sp. died out, while some strains of Desulfovibrio sp. and Clostridium sp. increased in concentration. In order to determine the minimum alkalinity value that the system could tolerate, the influent alkalinity was decreased from 1500 to 400 mg/L secondly. This resulted in the sulfate-removal rate, pH value and effluent alkalinity dropping quickly. The amount of Petrotoga sp., Prevotella sp., Kluyvera sp. and Neisseria sp. reduced obviously. The result data from Southern blotting indicated that the amount of sulfate-reducing bacteria (SRBs) decreased with influent alkalinity dropping. Analysis of the microbial community structure and diversity showed that the SRBs populations were very abundant in the inoculated activated sludge and the alkalinity decrease caused the reduction of the populations noted. Most of resident populations in the bioreactor were fermentative acidogenic bacteria (FABs), among which the phylum Firmicute was in the majority, but SRBs were very few. This community structure demonstrates the cooperation between SRBs and FABs, which sustains the system's high sulfate-removal and operation stability.

Bioreactors↗

PubMed2005

Crystal structure of a non-hemorrhagic fibrin(ogen)olytic metalloproteinase complexed with a novel natural tri-peptide inhibitor from venom of Agkistrodon acutus.

Thrombotic occlusive diseases pose a great threat to human health. Thrombolytic agents are in widespread use for the dissolution of arterial and venous pathologic thrombi in these kinds of diseases. Snake venom metalloproteinases (SVMPs) can act directly on fibrin/fibrinogen and are therefore potential candidates for therapeutic use against thrombotic occlusive diseases. In this study, we have determined the crystal structure of FII, a novel non-hemorrhagic SVMP isolated from Anhui Agkistrodon acutus snake venom by molecular replacement. The structure reveals that FII is a member of the P-I class SVMPs. The Zn2+ ion essential for hydrolytic activity is found in the active site and is tetrahedrally co-ordinated by three histidine residues and water molecule. Unambiguous electron density for a tri-peptide with sequence KNL is also found located near the active site. Biochemical evidences show that the tri-peptide KNL can inhibit the enzymatic activity of FII.

Amino Acid Sequence↗

PubMed2005

Crystal structure of the pyridoxal-5'-phosphate-dependent serine dehydratase from human liver.

L-serine dehydratase (SDH), a member of the beta-family of pyridoxal phosphate-dependent (PLP) enzymes, catalyzes the deamination of L-serine and L-threonine to yield pyruvate or 2-oxobutyrate. The crystal structure of L-serine dehydratase from human liver (hSDH) has been solved at 2.5 A-resolution by molecular replacement. The structure is a homodimer and reveals a fold typical for beta-family PLP-dependent enzymes. Each monomer serves as an active unit and is subdivided into two distinct domains: a small domain and a PLP-binding domain that covalently anchors the cofactor. Both domains show the typical open alpha/beta architecture of PLP enzymes. Comparison with the rSDH-(PLP-OMS) holo-enzyme reveals a large structural difference in active sites caused by the artifical O-methylserine. Furthermore, the activity of hSDH-PLP was assayed and it proved to show catalytic activity. That suggests that the structure of hSDH-PLP is the first structure of the active natural holo-SDH.

Amino Acid Sequence↗

PubMed2004

Crystallization and preliminary crystallographic studies of human coactosin-like protein (CLP).

The human coactosin-like protein (CLP) belongs to the actin-depolymerizing factor (ADF) family of actin-binding proteins. CLP interacts with 5-lipoxygenase (5LO) and filamentous actin (F-actin) via different binding sites. The full-length CLP comprising of 142 amino acids has been overexpressed in Escherichia coli. Crystals of CLP were obtained using the hanging-drop vapour-diffusion technique with ammonium sulfate as precipitant at pH 8.5. Diffraction data to 1.9 A resolution were collected from a crystal belonging to space group P2(1), with unit-cell parameters a = 25.6, b = 55.2, c = 37.4 A, beta = 96.0 degrees. There is one molecule per asymmetric unit.

Actins↗

PubMed2004

Characterization of the heptad repeat regions, HR1 and HR2, and design of a fusion core structure model of the spike protein from severe acute respiratory syndrome (SARS) coronavirus.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a newly emergent virus responsible for a worldwide epidemic in 2003. The coronavirus spike proteins belong to class I fusion proteins, and are characterized by the existence of two heptad repeat (HR) regions, HR1 and HR2. The HR1 region in coronaviruses is predicted to be considerably longer than that in other type I virus fusion proteins. Therefore the exact binding sequence to HR2 from the HR1 is not clear. In this study, we defined the region of HR1 that binds to HR2 by a series of biochemical and biophysical measures. Subsequently the defined HR1 (902-952) and HR2 (1145-1184) chains, which are different from previously defined binding regions, were linked together by a flexible linker to form a single-chain construct, 2-Helix. This protein was expressed in Escherichia coli and forms a typical six-helix coiled coil bundle. Highly conserved HR regions between mouse hepatitis virus (MHV) and SARS-CoV spike proteins suggest a similar three-dimensional structure for the two fusion cores. Here, we constructed a homology model for SARS coronavirus fusion core based on our biochemical analysis and determined the MHV fusion core structure. We also propose an important target site for fusion inhibitor design and several strategies, which have been successfully used in fusion inhibitor design for human immunodeficiency virus (HIV), for the treatment of SARS infection.

Amino Acid Sequence↗

PubMed2004

Crystal structure of human coactosin-like protein at 1.9 A resolution.

Human coactosin-like protein (CLP) shares high homology with coactosin, a filamentous (F)-actin binding protein, and interacts with 5LO and F-actin. As a tumor antigen, CLP is overexpressed in tumor tissue cells or cell lines, and the encoded epitopes can be recognized by cellular and humoral immune systems. To gain a better understanding of its various functions and interactions with related proteins, the crystal structure of CLP expressed in Escherichia coli has been determined to 1.9 A resolution. The structure features a central beta-sheet surrounded by helices, with two very tight hydrophobic cores on each side of the sheet. CLP belongs to the actin depolymerizing protein superfamily, and is similar to yeast cofilin and actophilin. Based on our structural analysis, we observed that CLP forms a polymer along the crystallographic b axis with the exact same repeat distance as F-actin. A model for the CLP polymer and F-actin binding has therefore been proposed.

Actins↗

PubMed2004

Crystal structure of severe acute respiratory syndrome coronavirus spike protein fusion core.

Severe acute respiratory syndrome coronavirus is a newly emergent virus responsible for a recent outbreak of an atypical pneumonia. The coronavirus spike protein, an enveloped glycoprotein essential for viral entry, belongs to the class I fusion proteins and is characterized by the presence of two heptad repeat (HR) regions, HR1 and HR2. These two regions are understood to form a fusion-active conformation similar to those of other typical viral fusion proteins. This hairpin structure likely juxtaposes the viral and cellular membranes, thus facilitating membrane fusion and subsequent viral entry. The fusion core protein of severe acute respiratory syndrome coronavirus spike protein was crystallized, and the structure was determined at 2.8 A of resolution. The fusion core is a six-helix bundle with three HR2 helices packed against the hydrophobic grooves on the surface of central coiled coil formed by three parallel HR1 helices in an oblique antiparallel manner. This structure shares significant similarity with the fusion core structure of mouse hepatitis virus spike protein and other viral fusion proteins, suggesting a conserved mechanism of membrane fusion. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation, which have been successfully used in human immunodeficiency virus 1 inhibitor development, may be applicable to the inhibition of severe acute respiratory syndrome coronavirus on the basis of structural information provided here. The relatively deep grooves on the surface of the central coiled coil will be a good target site for the design of viral fusion inhibitors.

Amino Acid Motifs↗

PubMed2004

Biochemical, biophysical and preliminary X-ray crystallographic analyses of the fusion core of Sendai virus F protein.

It is emerging that enveloped viruses may adopt a unique entry/fusion mechanism; in paramyxoviruses, including Sendai virus (SeV), the attachment protein HN (or its homologue H or G) binds a cellular receptor which triggers conformational changes of its fusion protein, F. There are at least three conformations of the F protein in the current fusion model: the pre-fusion native conformation, the pre-hairpin intermediate conformation and the post-fusion coiled-coil conformation. The fusion mechanism of SeV, a member of the Paramyxoviridae family, has been well established and several structural and functional domains or modules have been proposed from studies of its F protein. However, biochemical and biophysical studies of the heptad-repeat (HR) regions (HR1 and HR2) have not been systematically carried out. HR1 and HR2 strongly interact with each other to form a stable six-helix coiled-coil bundle as the post-fusion conformation. In this study, a single-chain HR1-linker-HR2 protein of SeV was prepared in an Escherichia coli expression system and biochemical and biophysical analyses showed it to form a typical six-helix coiled-coil bundle; its trigonal crystals diffracted X-rays to 2.5 A resolution. The crystal structure will help to reveal the structural requirements of the post-fusion coiled-coil conformation of SeV F protein.

Amino Acid Sequence↗

PubMed2004

Complex assembly, crystallization and preliminary X-ray crystallographic studies of MHC H-2Kd complexed with an HBV-core nonapeptide.

In order to establish a system for structural studies of the murine class I major histocompatibility antigen complex (MHC) H-2Kd, a bacterial expression system and in vitro refolding preparation of the complex of H-2Kd with human beta2m and the immunodominant peptide SYVNTNMGL from hepatitis B virus (HBV) core-protein residues 87-95 was employed. The complex (45 kDa) was crystallized; the crystals belong to space group P222(1), with unit-cell parameters a = 89.082, b = 110.398, c = 47.015 A, alpha = beta = gamma = 90 degrees. The crystals contain one complex per asymmetric unit and diffract X-rays to at least 2.06 A resolution. The structure has been solved by molecular replacement and is the first crystal structure of a peptide-H-2Kd complex.

Amino Acid Sequence↗

PubMed2004

3D structure of human FK506-binding protein 52: implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex.

FK506-binding protein 52 (FKBP52), which binds FK506 and possesses peptidylprolyl isomerase activity, is an important immunophilin involved in the heterocomplex of steroid receptors with heat-shock protein 90. Here we report the crystal structures of two overlapped fragments [N(1-260) and C(145-459)] of FKBP52 and the complex with a C-terminal pentapeptide from heat-shock protein 90. Based on the structures of these two overlapped fragments, the complete putative structure of FKBP52 can be defined. The structure of FKBP52 is composed of two consecutive FKBP domains, a tetratricopeptide repeat domain and a short helical domain beyond the final tetratricopeptide repeat motif. Key structural differences between FKBP52 and FKBP51, including the relative orientations of the four domains and some important residue substitutions, could account for the differential functions of FKBPs.

Amino Acid Sequence↗

PubMed2004

Crystallization and preliminary crystallographic analysis of the fusion core from two new zoonotic paramyxoviruses, Nipah virus and Hendra virus.

Highly conserved heptad-repeat (HR1 and HR2) regions in class I viral fusion (F) proteins, including the F protein from paramyxovirus, interact with each other post-fusion to form a six-helix bundle called a fusion core. Crystals of the fusion core of Nipah virus have been grown at 291 K using PEG 4000 as precipitant. The diffraction pattern of the crystal extends to 2.1 angstroms resolution at 100 K in-house. The crystals have unit-cell parameters a = 31.664, b = 31.725, c = 51.256 angstroms, alpha = 80.706, beta = 86.343, gamma = 65.812 degrees and belong to space group P1. Crystals of the fusion core of Hendra virus have also been grown at 291 K using PEG 4000 as precipitant. The diffraction pattern of the crystal extends to 2.0 angstroms resolution at 100 K in-house. A selenomethionine (SeMet) derivative of the HeV fusion core was overexpressed using the same Escherichia coli expression system and purified. The derivative crystals were obtained under similar conditions and three different wavelength data sets were collected to 2.0 angstroms resolution from the derivative crystal at BSRF (Beijing Synchrotron Radiation Facility). The crystals have unit-cell parameters a = 31.997, b = 31.970, c = 53.865 angstroms, alpha = 85.990, beta = 85.842, gamma = 68.245 degrees and belong to space group P1.

Crystallization↗

PubMed2004

EMG recurrence quantifications in dynamic exercise.

This study was designed to evaluate the suitability of nonlinear recurrence quantification analysis (RQA) in assessing electromyograph (EMG) signals during dynamic exercise. RQA has been proven to be effective in analyzing nonstationary signals. The subject group consisted of 19 male patients diagnosed with low back pain. EMG signals were recorded from left and right paraspinal muscles during isoinertial exercise both before and after 12 weeks of regimented physical therapy. Autorecurrence analysis was performed between the left and right EMG signals individually, and cross-recurrence analysis was performed on the left-right EMG pairs. Spectral analysis of the EMG signals was employed as an independent, objective measure of fatigue. Increase in the RQA variable % determinism during the 90-s dynamic tests was found to be a good marker for fatigue. Before physical therapy, this nonlinear marker revealed simultaneous increases in motor unit recruitment within each pool and between left and right pools. After physical therapy, the motor unit recruitment was less within and between pools, indicative of increased fatigue resistance. Finally, fatigue resistance (less increase in % determinism) correlated well with subjective scores of pain relief. Taken together, these latter results indicate that recurrence analysis may be useful in charting the efficacy of a specific exercise therapy program in reducing low back pain by elevating the fatigue threshold.

Electromyography↗

PubMed2004

Structural basis for coronavirus-mediated membrane fusion. Crystal structure of mouse hepatitis virus spike protein fusion core.

The surface transmembrane glycoprotein is responsible for mediating virion attachment to cell and subsequent virus-cell membrane fusion. However, the molecular mechanisms for the viral entry of coronaviruses remain poorly understood. The crystal structure of the fusion core of mouse hepatitis virus S protein, which represents the first fusion core structure of any coronavirus, reveals a central hydrophobic coiled coil trimer surrounded by three helices in an oblique, antiparallel manner. This structure shares significant similarity with both the low pH-induced conformation of influenza hemagglutinin and fusion core of HIV gp41, indicating that the structure represents a fusion-active state formed after several conformational changes. Our results also indicate that the mechanisms for the viral fusion of coronaviruses are similar to those of influenza virus and HIV. The coiled coil structure has unique features, which are different from other viral fusion cores. Highly conserved heptad repeat 1 (HR1) and HR2 regions in coronavirus spike proteins indicate a similar three-dimensional structure among these fusion cores and common mechanisms for the viral fusion. We have proposed the binding regions of HR1 and HR2 of other coronaviruses and a structure model of their fusion core based on our mouse hepatitis virus fusion core structure and sequence alignment. Drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of a number of emerging infectious diseases, including severe acute respiratory syndrome.

Amino Acid Motifs↗

PubMed2004

Expression, crystallization and preliminary X-ray studies of the recombinant PTB domain of mouse dok1 protein.

The PTB domain of mouse dok1 fusion protein has been overexpressed in Escherichia coli and crystallized in a form suitable for X-ray crystallographic study. Crystals have been obtained using the vapour-diffusion method and belong to space group P2(1)2(1)2(1). X-ray diffraction data were collected in-house to 2.5 A resolution. A selenomethionine (SeMet) dok1 PTB fusion-protein derivative was expressed using the same expression system, purified in a reductive environment and crystals were obtained under similar conditions. Subsequently, three different wavelength data sets from the derivative crystal were collected to 2.5 A resolution at SPring-8.

Animals↗